Methods and apparatus for intracranial ultrasound delivery

ABSTRACT

A method for delivering ultrasound energy to a patient&#39;s intracranial space involves forming at least one hole in the patient&#39;s skull, advancing at least one ultrasound delivery device at least partway through the hole(s), and transmitting ultrasound energy from the ultrasound delivery device(s). According to various embodiments, ultrasound delivery devices may be advanced into the epidural space, one or both ventricles and/or an intracerebral space of the patient&#39;s brain. In alternative embodiments, one or multiple holes may be formed in the skull, and any number of ultrasound delivery devices may be used. Intracranial ultrasound delivery may be used in diagnostic or therapeutic treatment of ischemic stroke, head trauma, atherosclerosis, perfusion disorders and other acute or chronic neurological conditions.

RELATED CASES

This is a continuation application of Ser. No. 11/203,738, filed Aug.15, 2005 now U.S. Pat. No. 7,717,853, which is a continuation-in-part ofSer. No. 11/165,872, filed Jun. 24, 2005, now abandoned, whosedisclosures are incorporated by this reference as though fully set forthherein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to medical methods andapparatus. More specifically, the invention relates to methods andapparatus for intracranial ultrasound delivery, which may includediagnostic ultrasound, therapeutic ultrasound or both.

Stroke is characterized by the sudden loss of circulation to an area ofthe brain, resulting in a corresponding loss of neurologic function.Also called cerebrovascular accident or stroke syndrome, stroke is anonspecific term encompassing a heterogeneous group of pathophysiologiccauses, including thrombosis, embolism, and hemorrhage. Strokescurrently are classified as either hemorrhagic or ischemic. Acuteischemic stroke refers to strokes caused by thrombosis or embolism andaccounts for 80% of all strokes.

More than 400,000 people per year in the U.S. have a first-time stroke.At current trends, this number is projected to increase to one millionper year by the year 2050. Stroke is the third leading cause of deathand the leading cause of disability in the U.S. Worldwide,cerebrovascular disease was the second leading cause of death in 1990,killing over 4.3 million people. Cerebrovascular disease was also thefifth leading cause of lost productivity, as measured bydisability-adjusted life years (DALYs). In 1990, cerebrovascular diseasecaused 38.5 million DALYs throughout the world. And although strokeoften is considered a disease of the elderly, 25% of strokes occur inpersons younger than 65 years. When the direct costs (care andtreatment) and the indirect costs (lost productivity) of strokes areconsidered together, strokes cost US society $43.3 billion per year.

Until very recently, almost nothing could be done to help patients withacute stroke. Little treatment existed for ischemic stroke until 1995,when the National Institute of Neurologic Disorders and Stroke (NINDS)recombinant tissue-type plasminogen activator (rt-PA) stroke study groupfirst reported that the early administration of rt-PA benefited somecarefully selected patients with acute ischemic stroke. Encouraged bythis breakthrough study and the subsequent approval of t-PA for use inacute ischemic stroke by the U.S. Food and Drug Administration,administration of t-PA has become increasingly more prevalent in stroketreatment. Treating patients early enough in the course of stroke,however, is an extremely challenging hurdle to effective treatment ofstroke. Furthermore, t-PA for stroke treatment is much more effective ifdelivered locally at the site of blood vessel blockage, but suchdelivery requires a great deal of skill and training, which only a smallhandful of medical professionals possess.

One proposed enhancement for treatment of stroke is the administrationof trans-cranial Doppler (TCD) at high frequencies (i.e., approximately2 MHz) and low intensities, which is normally used for diagnosticfunctions. TCD has been shown not only to be effective in visualizingclots, but also to be effective in lysing clots in the middle cerebralarteries, in combination with lytic drugs such as t-PA and/ormicrobubbles. TCD has also been shown to be safe, with no clinicallysignificant brain bleeding effects. (See, for example: A. V. Alexandrovet al., “Ultrasound-Enhanced Thrombolysis for Acute Ischemic Stroke,” N.Engl. J. Med. 351; 21, Nov. 18, 2004; and W. C. Culp and T. C McCowan,“Ultrasound Augmented Thrombolysis,” Current Medical Imaging Reviews,2005, 1, 5-12.) The primary challenge in using TCD to enhance stroketreatment, however, is that the skull attenuates the ultrasound signalto such a high degree that it is very difficult to deliverhigh-frequency, low-intensity signals through the skull. Using higherintensity ultrasound signals, in an attempt to better penetrate theskull, often causes unwanted bleeding of small intracranial bloodvessels and/or heating and sometimes burning of the scalp. The onlyother option is to carefully aim a high-frequency, low-intensity TCDsignal through a small window in the temporal bone of the skull toarrive at the middle cerebral artery, which is the technique describedin the studies cited above and is the only technique studied thus far.

There are two main drawbacks to delivering high-frequency TCD throughthe temporal window. First, such delivery requires a high level ofskill, and only a small handful of highly trained ultrasonographers arecurrently capable of performing this technique. Second, not allintracranial blood vessels are reachable with TCD via the temporalwindow. For example, although the temporal window approach may work wellfor addressing the middle cerebral artery, it may not work as well forreaching the anterior cerebral artery or various posterior intracranialarteries.

Assuming effective ultrasound delivery is achieved, in addition toenhancing treatment of acute thrombotic or embolic ischemic stroke, TCDmay also enhance and/or facilitate treatment of other cerebraldisorders. For example, recurrent lacunar strokes, dementia, head traumapatients with intracerebral blood clots or perfusion abnormalities, andeven Alzheimer's patients may benefit from TCD. In any such disorders,administration of TCD may help restore normal blood flow to the brain,help disperse harmful blood clots inside or outside blood vessels,and/or cause hyper-perfusion in one or more areas of the brain, thusenhancing cerebral function. For example, ultrasound administration hasbeen shown to enhance the production of nitric oxide in or nearby bloodvessels, which may thus cause vasodilation of nearby arteries andarterioles and enhance tissue perfusion. (See, for example, W. Steffenet al., “Catheter-Delivered High Intensity, Low Frequency UltrasoundInduces Vasodilation in Vivo,” European Heart Journal (1994) 15,369-376.) In any such treatments, however, use of TCD faces the samechallenges—i.e., it is very difficult to deliver at safe and effectivefrequencies to desired locations in the brain and thus can be performedonly by a small handful of highly skilled technicians and can bedirected only to a few areas in the brain. Also, the high intensitiesrequired to transmit ultrasound through the skull in TCD make itsutility for treating any chronic disorder impractical, since anyimplantable power source used with a chronic, implantable ultrasounddelivery device would be depleted too quickly.

Therefore, it would be desirable to have improved methods and apparatusfor intracranial delivery of ultrasound energy for diagnosticultrasound, therapeutic ultrasound, or both. Ideally, such techniqueswould be usable by a larger number of medical professionals than arecurrently qualified to administer TCD. Also ideally, such techniqueswould use ultrasound frequencies that do not cause unwanted bleeding inother blood vessels in the brain and that do not cause overheating orburning of the skin. At least some of these objectives will be met bythe present invention.

2. Background Art

U.S. Pat. No. RE36,939, issued to Tachibana et al., describes the use ofmicrobubbles to enhance the effects of ultrasound delivery, with orwithout a pharmacological composition. U.S. Pat. No. 6,006,123, issuedto Li et al., discloses use of ultrasound energy to enhancebioavailability of pharmaceutical agents. U.S. Pat. No. 5,399,158,issued to Lauer et al., describes a method of lysing thrombi, involvingadministration of t-PA or other plasminogen activators, with pulsed modeultrasound. U.S. Pat. No. 6,368,330, issued to Hynes et al., is directedto an apparatus for frameless stereotactic surgery.

BRIEF SUMMARY OF THE INVENTION

In one aspect of the present invention, a method for deliveringultrasound energy to a patient's intracranial space involves forming atleast one hole in the patient's skull, advancing at least one ultrasounddelivery device at least partway through the hole(s), and transmittingultrasound energy from the ultrasound delivery device(s). In someembodiments, one hole is placed in the skull, and one ultrasounddelivery device is used. In alternative embodiments, multiple holes areformed in the skull, and at least one ultrasound delivery device isadvanced at least partway through each hole. In other alternativeembodiments, one hole is formed in the skull, and multiple ultrasounddelivery devices are advanced through the hole.

The hole (or holes) in the patient's skull may be formed using anysuitable devices and methods. For example, in some embodiments a hand orpower drill or burr device may be used, such as those commonly known inthe art for forming holes in the skull. Once a hole is formed in theskull, one or more ultrasound delivery devices may be advanced partwayor completely into the hole or through the hole. In one embodiment, forexample, a delivery device is placed into the hole so a distal end ofthe device is flush with the inner wall of the skull. In otheralternative embodiments, one or more delivery devices are advancedthrough the hole(s) into the epidural space, one or more ventriclesand/or an intracerebral space of the patient's brain. For the purposesof this application, “intracerebral space” means any location withinbrain tissue or parenchyma outside of blood vessels.

To facilitate introduction of ultrasound delivery devices through one ormore holes in the patient's skull, one or more introducer devices mayoptionally be used. For example, in one embodiment an introducer deviceis placed at least partway into a hole, and at least one ultrasounddelivery device is advanced partway or all the way through theintroducer device. In one alternative embodiment, the introducer deviceis advanced through a hole and into the patient's epidural space, andone or more ultrasound devices are thus advanced into the epiduralspace. In other alternative embodiments, the introducer device may beadvanced through the hole and into a ventricle or an intracerebral spaceof the patient's brain, and one or more ultrasound devices are thusadvanced into the ventricle or intracerebral space.

Any suitable ultrasound delivery device may be used in implementingvarious embodiments of the present invention. For example, in oneembodiment, the device may comprise an ultrasound transducer. In anotherembodiment, the device comprises a transducer-tipped ultrasoundcatheter. In either case, the ultrasound transducers may be formed frompiezoelectric crystal or from silicon-based ultrasonic transducertechnology.

In many embodiments, the ultrasound energy is transmitted acutely, suchas in treatment of ischemic stroke or acute head trauma. In alternativeembodiments, the ultrasound energy may be transmitted chronically, suchas in treatment of chronic brain perfusion disorders. In some cases, adevice or part of a device may be implanted in the patient for chronictreatment. In various embodiments, any of a number of differentconditions may be treated or ameliorated with the methods of theinvention. For example, the ultrasound energy may be transmitted to ablood clot, either within or outside of a blood vessel, to help disruptthe clot. In another embodiment, the energy may be transmitted to ablood vessel to treat atherosclerosis of the vessel. In otherembodiments, the energy may be transmitted to one or more blood vesselsin the brain to help treat any of a number of blood perfusionabnormalities.

Optionally, the method may further include providing one or morepharmacologic agents to the patient, in conjunction with the deliveredultrasound energy. Examples of such agents include, but are not limitedto, tissue plasminogen activator and other blood clot reducing agents,such as rTPA, Urokinease, Streptase (Streptokinase) Actiase (Alteplase)and Desmoteplase. Other agents which may be used include antiplateletagents such as aspirin, Plavix (clopidorgel) and Ticlid (Ticclopidine),and GIIb/IIIa inhibitors, such as Reopro (abciximab), Aggrestat(Tirofiban) and Integrilin (eptifibatide). Such a pharmacologic agentmay be delivered intravenously, arterially, via intramuscular injection,or orally, in various embodiments. Alternative methods optionallyinvolve delivering microbubbles or nanobubbles into the patient'sbloodstream, in conjunction with the delivered ultrasound energy. Suchmicrobubbles or nanobubbles may be delivered intravenously orarterially. In some embodiments, both microbubbles or nanobubbles and apharmacologic agent may be delivered to the patient along with theultrasound energy.

Once one or more holes have been formed in the skull, ultrasound energymay be transmitted from any of several locations and in any of a numberof different patterns. For example, in one embodiment, multiple holesare formed in the patient's skull, and ultrasound energy is transmittedfrom multiple delivery devices at multiple locations simultaneously.Such a delivery pattern may be advantageous, for example, intriangulating the ultrasound transmissions toward the same target. In analternative embodiment, ultrasound energy is delivered sequentially frommultiple delivery devices. In some cases, the ultrasound energy istransmitted from multiple delivery devices with the same frequency andintensity. Alternatively, the ultrasound energy may be transmitted frommultiple delivery devices with different frequencies, differentintensities and/or different modes. Ultrasound energy may be transmittedat any desired frequency, although in preferred embodiments the energyhas a frequency between about 10 KHz and about 20 MHz, and morepreferably between about 17 KHz and about 10 MHz. According to differentembodiments, the ultrasound energy may be transmitted in continuous modeor pulse mode or may be modulated.

At any point during or after advancement of an ultrasound device througha hole in the skull, the location of the device may be monitored via anysuitable visualization apparatus. For example, radiographic, computedtomography (CT) or magnetic resonance imaging (MRI) technologies may beused to help facilitate placement of an ultrasound delivery device in adesired location. In some embodiments, radiographs, CT images and/or MRIimages may be used before device placement to determine an ideallocation for the device. In some embodiments, during ultrasound energydelivery to the target site in the brain, patient recovery status may bemonitored using one or more sensing methods, such as but not limited tomonitoring of oxygen levels or saturation, rate of carbon dioxideproduction, heart rate, intracranial pressure and/or blood pressure.Also, the sensing element's measure could be used to modulate theintensity, frequency and/or duty cycle of the ultrasonic device(s). Sucha feedback process is also known as a closed loop control system. Someembodiments may also include the use of a disposable patient interface(DPI), a sterile, compliant conductive gel/oil pack which interfacesbetween the ultrasound transducer and the patient.

In another aspect of the present invention, a method for deliveringultrasound energy from within a patient's epidural space involvesadvancing at least one ultrasound delivery device through at least onehole in the patient's skull to locate at least a distal portion of thedevice in the patient's epidural space and transmitting ultrasoundenergy from the ultrasound delivery device(s). Such a method may furtherinvolve forming the hole(s) in the patient's skull. According to variousembodiments, any of the features or variations of the methods describedabove may be implemented.

In another aspect of the present invention, a method for deliveringultrasound energy from within at least one ventricle of a patient'sbrain involves advancing at least one ultrasound delivery device throughat least one hole in the patient's skull to locate at least a distalportion of the device in at least one ventricle of the patient's brainand transmitting ultrasound energy from the ultrasound deliverydevice(s). Again, such a method may further include forming the hole(s)in the patient's skull. Any of the features or variations describedabove may be implemented in various embodiments.

In another aspect of the present invention, a method for deliveringultrasound energy from within an intracerebral space of a patient'sbrain involves advancing at least one ultrasound delivery device throughat least one hole in the patient's skull to locate at least a distalportion of the device an intracerebral space of the patient's brain andtransmitting ultrasound energy from the ultrasound delivery device(s).The method may further include forming the hole(s) in the patient'sskull. And again, any of the features or variations described above maybe implemented, according to various embodiments. Delivery of ultrasoundenergy from the intracerebral space may be used for treatment of any ofa number of conditions, such as acute clot outside of blood vesselscaused by brain trauma or ischemic stroke caused by a clot within avessel. In various embodiments, ultrasound may be combined with deliveryof a pharmacological agent, microbubbles/nanobubbles or both.Ultrasound, with or without additional agents, may be delivered untilthe patient's symptoms improve and/or until a brain imaging study (e.g.MR, CT, PET, SPECT) demonstrate that the adverse “mass effects” of aclot outside are significantly reduced (e.g., <10% in size). Fortreatment of clot inside a vessel, as in ischemic stroke patients, theultrasound delivery device may be placed near or directly adjacent tothe clotted blood vessel.

Further aspects and embodiments of the present invention are describedin greater detail below, with reference to the attached drawing figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of a portion of a human skull, showingthe skull, brain tissue and epidural space and a hole formed in theskull with an introducer device in place, according to one embodiment ofthe present invention.

FIG. 2A is a cross-sectional view as in FIG. 1, with multiple ultrasounddelivery devices advanced through the introducer device into theepidural space, according to one embodiment of the present invention.

FIG. 2B is a top view of the introducer device and ultrasound deliverydevices of FIG. 2A.

FIG. 2C is a cross-sectional view as in FIG. 1, with multiplecatheter-based ultrasound delivery devices advanced through theintroducer device into the epidural space, according to an alternativeembodiment of the present invention.

FIG. 3 is a cross-sectional view of a human skull with a hole formedtherein and with an ultrasound transducer device in place within thehole, according to an alternative embodiment of the present invention.

FIG. 4 is a cross-sectional view of a human skull and brain, showing anultrasound delivery device advanced through a hole in the skull and intoa ventricle of the brain, according to one embodiment of the presentinvention.

FIG. 5 is a cross-sectional view of a human skull and brain, showing anultrasound delivery device advanced through a hole in the skull and intoa ventricle of the brain, according to an alternative embodiment of thepresent invention.

FIG. 6 is a frontal diagrammatic view of a human torso and head,demonstrating an implantable ultrasound delivery system for chronictreatments, according to one embodiment of the present invention.

FIG. 7 is a side view of a human head with three ultrasound transducerscoupled therewith, demonstrating a triangulation technique fordelivering ultrasound energy to a location in the brain, according toone embodiment of the present invention.

FIG. 8 is a cross-sectional view of a human skull and brain, showing anultrasound delivery device advanced through a hole in the skull and intoan intracerebral space of the brain, according to an alternativeembodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Methods and apparatus of the present invention generally involvedelivering ultrasound energy to a patient's intracranial space fordiagnostic purposes, or therapeutic treatment, or both. The methodsinvolve forming at least one hole in the patient's skull, advancing atleast one ultrasound delivery device at least partway through thehole(s), and transmitting ultrasound energy from the ultrasound deliverydevice(s). In some instances, such as in treatment of ischemic stroke,ultrasound energy is delivered to a target clot in a blood vessel. Inother cases, such as in acute head trauma, ultrasound energy may bedirected toward an extravascular blood clot in the brain. In othercases, energy may be delivered toward an area of blood vessels to causevasodilation and thus increased blood flow. Thus, the techniques andapparatus described herein may be used for a number of differentapplications and treatments and are not limited, for example, totreatment of an isolated intracranial blood clot or even to ischemicstroke therapy.

With reference now to FIG. 1, a cross-sectional view of a portion of ahuman head is shown, with a skull Sk, epidural space ES, dura mater D,subarachnoid space SS, pia mater P and brain tissue B. In variousembodiments, one or more holes 12 or openings are formed in the skull Skusing any suitable hole forming device, such as but not limited to apower drill, hand drill, or burr device. In some embodiments, a guidedevice 10 (or “introducer”) is placed in hole 12 to facilitate deliveryof one or more ultrasound delivery devices. In alternative embodiments,guide device 10 is not used. Hole(s) and the opening of guide device 10may have any desired diameters. For example, the opening of guide device10 may have a diameter d ranging from about 0.5 mm to about 20.0 mm inone embodiment.

Guide device 10 may be attached to the skull Sk by any suitable means.In some embodiments, for example, guide device 10 is pressure fittedwithin hole 12, while in other embodiments guide device 10 may havethreads for screwing into hole 12 or may include a locking mechanism forattaching to the skull Sk. In some embodiments, one or more atraumaticguide catheters (not shown) may be used with guide device 10 tointroduce one or more ultrasound delivery devices into hole 12 or intothe epidural space ES. Use of such a guide catheter may help ensure thatno intracranial structures are damaged.

Referring now to FIGS. 2A and 2B, in one embodiment, two ultrasounddelivery leads 14, each having a transducer 16 (or “ultrasound wand”)coupled to its distal end, may be delivered through guide device 10 intothe epidural space ES. Transducers 16 may then rest on the dura mater Dor float within the epidural space ES, and ultrasound energy may then betransmitted from the wands into the intracranial space. Transducers 16may be delivered through a microcatheter or via any other suitabledelivery technique. Furthermore, any number of ultrasound delivery leads14 and transducers 16 may be delivered through hole 12, such as from oneto ten leads 14 and transducers 16. FIG. 2B shows introducer 10; leads14 and transducers 16 from a top view.

Referring now to FIG. 2C, an alternative embodiment is shown in whichmultiple ultrasound catheters 18 are delivered through hole 12 into theepidural space ES. Each ultrasound catheter 18 includes a distalultrasound transducer 20, which transmits ultrasound energy into theintracranial space. Again, any number of catheters 18 may be introducedthrough one hole, such as anywhere from one to ten catheters 18.Catheter 18 may be an over-the-wire or not over-the-wire, in variousembodiments. Each catheter 18 may include one ultrasound transducer 20or may include multiple transducers 20 distributed along its distalportion. In one embodiment, a distal portion of catheter 18 may have astraight configuration when being delivered but may then assume ahelical shape when deployed in the epidural space ES, with the helixhaving a larger diameter than hole 12. The helical portion may thencontain multiple transducers to allow transmission of ultrasound inmultiple different directions. Catheter 18 also have a deflectable tipto allow it to be moved to various locations within the epidural spaceES without causing damage. Transducers 20 may be formed frompiezoelectric crystal or using chip technology. In some embodiments, forexample, transducers 20 may be fabricated on the surface of a siliconwafer.

With reference now to FIG. 3, in an alternative embodiment, nointroducer or guide device is used. Instead, an ultrasound transducer 22with an ultrasound delivery tip 24 and coupled to a power supply via alead 26 is placed directly within hole 12 in the skull. Transducer 22may extend only partway into hole 12 or alternatively may extend all theway into hole 12 or even extend into the epidural space ES, as shown.Transducer 22 is then used to deliver ultrasound energy to theintracranial space.

In any of the embodiments described above, any desired number of holes12 may be formed in the skull Sk and any desired number of ultrasounddelivery devices may be inserted into the holes to deliver ultrasoundenergy. For example, in some embodiments one hole 12 is formed and onedelivery device is used. In another embodiment, one hole 12 may beformed and multiple delivery devices inserted through that hole 12. Inother alternative embodiments, multiple holes 12 are formed and eitherone or multiple delivery devices may be placed through each hole. Asdescribed further below, forming multiple holes and using multipleultrasound delivery devices may be advantageous in some cases in that itallows for the delivery of ultrasound energy from multiple anglessimultaneously or in succession.

Referring to FIG. 4, in some embodiments, a catheter device 40 may beused to advance an ultrasound delivery wand 46 into a ventricle V of abrain B. In one embodiment, catheter 40 includes a hub 42, a cathetershaft 43, a lead 44 and wand 46 attached to the distal end of lead 44.As shown, catheter 40 extends through the scalp S, skull Sk, epiduralspace ES, dura mater D, subarachnoid space SS, pia mater P and braintissue B to enter the ventricle V. Hub 42 may rest under the scalp S, asshown, or on top of the scalp S, in various embodiments. Catheter 40 isfully retrievable, so that the wand 46, lead 44, catheter shaft 43 andhub 42 may be easily removed from the patient. Delivering ultrasoundenergy from within a ventricle V in the brain B may be very advantageousin some cases, depending on the location of the target treatment area.

With reference now to FIG. 5, an alternative embodiment of an ultrasounddelivery device 50 for delivering energy from within a ventricle V isshown. In this embodiment, delivery device 50 includes a hub 52, acatheter shaft 54, a wand 56 at or near the distal end of catheter shaft54, and a lead 58 coupling device 50 to a power supply. In someembodiments, catheter shaft 54 is steerable, to facilitate delivery ofwand 56 into the ventricle V. In various embodiments, hub 52 may resideeither outside or inside the scalp S.

In either of the intraventricular approaches just described, or in anyother intraventricular approach, the catheter may be placed blindly, viabony landmarks, into one of the ventricles of the brain via atraditional ventriculostomy approach. After forming a hole in the skull,the catheter or guidewire system is placed into the ventricle. Whenclear cerebrospinal fluid flows out of the proximal end of the catheter,the physician knows the distal end of the catheter is in the ventricle.In an alternative embodiment, intraoperative computed tomography (CT)imaging may be used to help guide placement of the catheter. In anotherembodiment, preoperative CT and/or MRI scanning may be used with animage-guided system to help guide the catheter into the ventricle. Suchimage guided systems are provided, for example, by Medtronic, Inc., orBrainLAB, Inc. Once the catheter is placed in the ventricle, one or moretransducers may be advanced through the catheter, as in the embodimentshown in FIG. 4. Alternatively, one or more transducers may be includedat or near the distal end of the catheter, as in the embodiment shown inFIG. 5.

Referring now to FIG. 6, for some treatments it may be desirable toimplant one or more ultrasound delivery devices in a patient and use thedevices for chronic therapy. Such implantable devices may be used, forexample, in treating Alzheimer's disease or a chronic brain perfusiondisorder, or in increasing perfusion over time to enhance brainfunction. In one embodiment, an implantable ultrasound delivery system60 includes multiple ultrasound delivery devices 61, coupled withmultiple leads 62, which may be tunneled under the scalp and skin to animplanted power source 64 in the chest. In an alternative embodiment,power source 64 may be implanted under the patient's scalp or eveninside the patient's skull. One type of intracranial implantable powersupply, for example, is provided by Neuro Pace, Inc. Types ofimplantable power sources include standard lithium ion non-rechargeableor rechargeable batteries. In an another alternative embodiment, thepower source 64 could be located external to the body and would transmitthe power to an implanted receiver coil in the patient via radiofrequency energy. The implantable receiver coil would convert the powerinto the appropriate form and be connected to the ultrasound systemwires. Ultrasound delivery devices 61 may then deliver continuous orintermittent ultrasound energy to one or more intracranial target areasto enhance blood flow. Each device 61 is placed within a hole formed inthe skull.

As mentioned above, and with reference now to FIG. 7, in some embodimentmultiple ultrasound delivery devices 70 are placed in multiple holes ina patient's skull to deliver ultrasound energy to an intracranial targetarea from multiple angles. In the embodiment shown, three deliverydevices 70 a-70 c are used to direct energy toward a blockage B in themiddle cerebral artery MCA. Triangulation of ultrasound energy signalsin this way typically enhances the ability of the energy to break up ablockage B. In embodiments where multiple ultrasound devices 70 areused, energy may be transmitted from devices 70 either simultaneously orat different times. In some embodiments, for example, energy may betransmitted sequentially.

In one embodiment of the triangulation method described by FIG. 7,preoperative CT/CTA (computed tomography angiography) and/or MR/MRA(magnetic resonance angiography) images are obtained of the patient'sintracranial space. These images are obtained with some type offiduciaries on the patient's head, such as screw-on or stick-onfiduciaries. Once the images are obtained and a clot locationidentified, computer software may be used to recommend where to locatethe ultrasound delivery devices on the skull or within the epiduralspace or ventricular space(s). Based on the software recommendations,multiple delivery devices are then placed, typically though notnecessarily three or more devices. The ultrasound transducer(s) could bemade of MR and/or CT compatible materials so that the related heating orimaging artifacts are minimized during scans. It is important thattransducer(s) is made of MR/CT compatible materials because patientswith acute stroke may need to be imaged, scanned multiple times toaccess recovery progress.

In any of the embodiments described above, any desired ultrasoundfrequency and intensity may be delivered, and ultrasound energy may bedelivered in continuous mode, pulsed mode, or a combination thereof. Invarious embodiments, for example, ultrasound frequencies of betweenabout 20 KHz and about 10 MHz may be used. When pulse mode is used, thepulse mode may vary from about 1% to about 99% of the duty cycle.

Additionally, in various embodiments, ultrasound energy may be deliveredalong With intravenous or intraarterial drug delivery and/or intravenousdelivery of microbubbles or nanobubbles. For example, ultrasound may bedelivered along with tissue plasminogen activator and other blood clotreducing agents, such as rTPA, Urokinease, Streptase (Streptokinase)Actiase (Alteplase) and Desmoteplase. Other agents which may be usedinclude antiplatelet agents such as aspirin, Plavix (clopidorgel) andTiclid (Ticclopidine), and GIIb/IIIa inhibitors, such as Reopro(abciximab), Aggrestat (Tirofiban) and Integrilin (eptifibatide).Microbubbles or nanobubbles of lipids or other suitable substances mayalso be used.

Once a procedure is completed and the ultrasound delivery device(s) areremoved, the hole(s) in the skull may be filled using any suitabletechnique, such as with known techniques using plugs or bands.

Referring now to FIG. 8, in some embodiments, a catheter device 80 maybe advanced through a hole in a patient's skull Sk so that an ultrasoundtransducer 86 of device 80 is located in the intracerbral space of thepatient's brain B. In one embodiment, catheter device 80 includes a hub82, a catheter shaft 84, ultrasound transducer 86, and a lead 88connecting device 80 to a power supply. As shown, catheter device 80extends through the scalp S, skull Sk, epidural space ES, dura mater D,subarachnoid space SS, and pia mater P and into brain tissue B. Hub 82may reside outside the scalp S, as shown, or under the scalp S, invarious embodiments. Catheter device 80 is fully retrievable. Deliveringultrasound energy from within the intracerebral space in the brain B maybe very advantageous in some cases, such as in treatment of acutehemorrhage and/or clot caused by head trauma.

Although the invention has been described fully above, a number ofvariations and alterations could be made within the scope of the presentinvention. For example, in alternative embodiments, steps in the variousdescribed methods may be carried out in different orders or skippedaltogether, and in other embodiments, additional optional steps may beadded or one or more steps may be altered. Therefore, the foregoingdescription of exemplary embodiments should not be interpreted to limitthe scope of the invention described by the following claims.

1. A method for delivering ultrasound energy to a patient's intracranialspace, the method comprising: forming at least one hole in the patient'sskull to access a target location; placing an introducer device into theat least one hole to a treatment location within the target location;advancing at least one ultrasound device having a distal portion throughthe introducer device, wherein the distal portion of the ultrasounddevice contains at least one transducer to allow transmission ofultrasound, and the distal portion can be moved to various locationswithin the intracranial space; positioning the distal portion at aselected location within the intracranial space; transmitting ultrasoundenergy at frequencies between 10 KHz and 10 MHz from the ultrasounddevice for therapeutic treatment; and transmitting and directing theultrasound energy to a blood clot in the patient's brain at the targetlocation that resides in an intracranial space of the patient's brain,wherein the blood clot is located outside a blood vessel.
 2. The methodof claim 1, wherein the blood clot resides in the intracerebral locationof the intracranial space.
 3. The method of claim 1, wherein the bloodclot resides underneath the dura mater located within the intracranialspace.
 4. The method of claim 1, wherein the blood clot resides in theepidural location of the intracranial space.
 5. The method of claim 1,wherein advancing the at least one ultrasound device comprises advancingthe device into the patient's epidural space.
 6. The method of claim 1,wherein advancing the at least one ultrasound device comprises advancingthe device into at least one ventricle of the patient's brain.
 7. Themethod of claim 1, wherein advancing the at least one ultrasound devicecomprises advancing the device into an intracerebral space of thepatient's brain.
 8. The method of claim 1, wherein advancing the atleast one ultrasound device comprises advancing the device underneaththe dura mater of the patient's brain.
 9. The method of claim 1, whereinadvancing the ultrasound device comprises advancing a device selectedfrom the group consisting of an ultrasound transducer and atransducer-tipped ultrasound catheter.
 10. The method of claim 1,further comprising delivering at least one pharmacologic agent to thepatient intracranial space.
 11. The method of claim 1, furthercomprising delivering microbubbles or nanobubbles.
 12. The method ofclaim 1, further including removing blood clots to the outside the head.